Retrospective and Prospective Case Review of Chronic Inflammatory Demyelinating Polyradiculoneuropathy at the Johannesburg Hospital

Transcription

1 Retrospective and Prospective Case Review of Chronic Inflammatory Demyelinating Polyradiculoneuropathy at the Johannesburg Hospital Dr David G Anderson University of the Witwatersrand Department of Neurosciences Division of Neurology A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science in Medicine in Neurology. Johannesburg

2 Declaration I, David Graham Anderson, declare that this research report is my own work. It is being submitted for the degree of Master of Science in Medicine in the division of Neurology, at the University of the Witwatersrand, Johannesburg. This work has never been submitted before for any degree or examination at this or any other university. David Graham Anderson Day of

3 Details Title A Retrospective and Prospective Case Review of Chronic Inflammatory Demyelinating Polyradiculoneuropathy at the Johannesburg Hospital Contact Details Student Name: David Graham Anderson Student Number: R Office Number: Cell Number: dganderson@mweb.co.za Ethics Number M Supervisors Primary supervisor Dr Andre Mochan Contact: Secondary Supervisor Professor Girish Modi Contact:

4 Dedication This dissertation has been 3 years in the making and has been hard fought. I have much to be thankful for and many people to thank. Firstly my supervisors: To Andre Mochan, who nurtured my love of peripheral neurology and guided me through this thesis. You have been both a mentor and a friend. To Prof Modi, thank you for the spark that triggered my interest in CIDP, the hours of putting up with my bad English and helping me to be the Neurologist I am today. I need to thank the entire Neurology Department at the Johannesburg Hospital, Chris Hani Baragwanith and Helen Joseph for all the referrals and tolerance that you showed with my obsession. A special thanks to Mrs. Cook and Myles Connor who kept me sane at full moon. The neurophysiology department knows more about CIDP than most. Thank you for putting up with my banter and special thanks to Khadija for always keeping the machines warmed up for me. To the staff of 586, I would go home and you would be the ones to stay and take care of all these patients. You have been my teachers and my family for the last four years and for this I will be eternally grateful. My friends have been very patient for many years now. When I would want to work they would wait, but only round the corner. Adam, Brett, Dion, Pia and Jed, thank you. To Tony for all the crossed t s... I am forever in your debt. To my family: I am everything and have everything today because of you. To my beautiful sister thank you for your love and support. I dedicate this MMED to my Mom and Dad. Thank you for being my anchor and my sail. 4

5 Abbreviations AAN- American Academy of Neurologists ACTH- Adrenocorticotropic Hormone AIDP- Acute Inflammatory Demyelinating Polyneuropathy AIDS- Acquired immune Deficiency Syndrome BBB- Blood Brain Barrier CIDP- Chronic Inflammatory Demyelinating Polyneuropathy CMAP- Compound Muscle Action Potential CSF- Cerebrospinal Fluid DADS- Distal Acquired Demyelinating Symmetrical EFNS- European Federation of Neurological Societies ESR- Erythrocyte Sedimentation Rates FBC- Full Blood Count GALOP- Gait disorder Auto antibody Late age Onset Polyneuropathy HIV- Human immunodeficiency virus INCAT- Inflammatory Neuropathy Cause And Treatment MADSAM-Multi-focal Acquired Demyelinating Sensory And Motor MGUS- Monoclonal gammopathy of unknown significance MMN- Multifocal Motor Neuropathy POEMS- Polyneuropathy Organomegaly Endocrineopathy M-protein Skin changes TNF- Tumour Necrosis Factor 5

6 Index Declaration... 2 Details... 3 Dedication... 4 Abbreviations Introduction Definition Literature Review Historical Background Epidemiology... 9 Table 1: Comparison of demographic information of CIDP Development of diagnostic criteria to aid the diagnosis of CIDP Table 2: Comparison of the diagnostic criteria of CIDP (Adapted from Koller et al.) Pathophysiology Pathology Disease course CIDP Subtypes Table 4: CIDP subtypes (Adapted from CIDP and concurrent illness Treatment Prognosis Aim of the Study Design Population and case ascertainment

7 3.2. Duration of the study Assessment of patients Inclusion Criteria Ethics Statistical analysis Results Demographics Graph Latency Course Motor findings Sensory Findings Cerebrospinal Fluid Findings Graph Table 6. Blood Brain Barrier results Concurrent illness Electrophysiology Table 5: Nerve Motor Conduction Velocity results Antibodies HIV and CIDP Demographics History and course of weakness CIDP Subtype Motor Sensory Cerebrospinal fluid

8 5.1. Demographics Gender Ratio Ethnicity Age Latency Course Motor Sensory Cerebrospinal fluid Concurrent illness Antibodies HIV and CIDP Conclusion Search References for Search Search References for Search 2:

9 1. Introduction 1.1. Definition Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) is an immune mediated neuropathy with variable presentations, ranging from symmetrical paralysis to a variety of focal manifestations and which may progress slowly or in a fluctuating pattern. (Dyck, Lais, Ohta et al., 1975) Literature Review Historical Background A description of CIDP first appeared in the literature more than half a century after Guillain, Barré and Strohl described areflexic ascending paralysis. James Austin first reported two cases of ACTH-responsive polyneuropathy and reviewed the findings in nine other cases (Austin, 1958). Twenty-seven years later Peter J Dyck et al. described in great detail 53 patients with an ascending progressive paralysis from the Mayo Clinic (Dyck et al, 1975) Epidemiology Epidemiological studies for CIDP are few. A large community based study from southeast England Four Thames area found the adult prevalence to be 1 per (Lunn, Manji, Choudhary et al, 1999) (table 1). A second study in New South Wales, Australia, found the 9

10 adult CIDP community-based prevalence to be 1.9 per (McLeod, Pollard, Macaskill et al, 1999). The data from the Australian study was then used in a separate study to work out the childhood crude prevalence as 0,46 per , where childhood was defined as aged below 20 years (Connolly, 2001). A study based in Norway used a county neuropathy database to estimate prevalence of CIDP at 7.7 per (Mygland & Monstad, 2001). In this retrospective study there was the potential for selection bias as it was a hospital based study using a specialised neuropathy unit s database and this was then correlated with the area s population and therefore this figure may be an over estimation. There are no studies for CIDP in Africa (Search 1-Apendix page 49). The bulk of the demographic profile of CIDP comes from the two descriptive papers by Dyck et al. (1976) and Barohn et al. (1989) and the three prevalence studies mentioned above. In these studies there was a male predominance with peak onset in the 5 th decade. Ethnicity was not reported in these studies or elsewhere in the literature. (Table 1. Comparison of demographic information of CIDP.) Table 1: Comparison of demographic information of CIDP Dyck et al. Barohn et al. Lunn et al. McLeod et al. Mygland et al. Total number of patients Age in years (Mean ± SD) * Range ± 17 Range ± 17.7 Range ± 20.1 Range (no SD) Males 35 (66%) 35 (58%) 26 (57%) 64 (57%) 11 (73%) Females 18 (34%) 25 (42%) 20 (43%) 48 (43%) 4 (27%) F:M ratio 1 : : : : :

11 * No mean was available from this paper but the highest frequency of the disorder was reported in the 5 th and 6 th decade Development of diagnostic criteria to aid the diagnosis of CIDP In Dyck s paper the distinction was made between idiopathic inflammatory polyradiculopathies and those associated with systemic illness because this was helpful in making the diagnosis and in predicting out come. It also divided them into motor, sensory and mixed types. A time frame of 6 months before the neurological deficit had crested was used to divide the neuropathies into acute and chronic. The chronic form was then found to follow a steadily progressive, recurrent, stepwise progressive or monophasic course (Dyck et al, 1975). The diagnostic criteria evolved during the decade that the Mayo group collected their data. (1) No toxic or other disease could explain the neuropathy. (2) There was a history of preceding illness or immunization. (3) The patient had neurological deterioration that continued beyond 6 months. (4) Involvement was usually symmetrical, with proximal and distal weakness seen. (5) Papilloedema and essential tremor are occasionally seen. (6) Electrodiagnostic study conduction velocities are generally slowed and may even be blocked proximally and there is often a disproportion between clinical signs and nerve conductions. (7) There is cytoalbuminologic dissociation at some point during the course of the illness and the ү-globulin may be elevated in the CSF. (8) Full blood count (FBC) and erythrocyte sedimentation rates (ESR) are normal. Many of these criteria have stood the test of time. 11

12 Since Dyck s seminal paper there have been many attempts to redefine the definitions and the diagnostic criteria for CIDP. A sensitive and specific set of diagnostic criteria is important because CIDP represents up to 21% of undiagnosed neuropathies and is a treatable condition (Dyck, Oviatt, & Lambert, 1981). By increasing the number of patients diagnosed, more patients could get treated and therefore avoid the chronic morbidity associated with this condition. In 1989 an American group published a retrospective report of 60 patients with CIDP seen in the Neuromuscular Division at the Ohio State University over a ten-year period (Barohn, Kissel, Warmolts et al, 1989). Recommendations were given to expand the only diagnostic criteria for CIDP that had been published at that time. These new criteria were broader and therefore would allow for the heterogeneity seen in CIDP. One of the changes was the to the to the progression of weakness beyond 6 months. This was reduced to 2 months because they found that no patients with Acute Inflammatory Demyelinating Polyneuropathy (AIDP) showed progression of weakness after 6 weeks (Mendell, Barohn, Freimer et al, 2001). This had the advantage of allowing earlier treatment of CIDP. Later, an American Academy of Neurologists (AAN) task force developed diagnostic criteria that are based on the history, neurological examination and nerve conduction studies (Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force, 1991). Cerebrospinal fluid analysis and sural nerve biopsy are mandatory for the diagnosis of CIDP when using the AAN criteria. 12

13 The clinical features first described by Dyck are common to all currently available diagnostic criteria (Dyck et al., 1975; Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. 1991) All criteria require a patient to have at least two months of progressive weakness, and symmetrical proximal and distal weakness is considered a major diagnostic feature. The hallmark of CIDP is hyporeflexia or areflexia. Although CIDP is a predominantly motor condition, the majority of CIDP patients also have at least some sensory involvement. Numbness to pain and temperature testing may be present in a stocking distribution and there may be associated paraesthesias in the same regions. Proprioception may be lost in the lower limbs in classical CIDP (Dyck et al, 1975; Barohn et al, 1989). The AAN electrophysiological criteria require at least 3 of the following four criteria: (1) Partial conduction block must be present in at least 1 motor nerve. This may be subdivided into definite, probably or possible partial conduction block and defined as a greater than 20% drop in negative peak area or peak-to-peak amplitude, plus a less than 15% change in duration between proximal and distal sites (partial conduction block) or a greater than 15% change in duration between proximal and distal sites (possible conduction block/temporal dispersion). Conduction block and temporal dispersion are only considered in the following nerve segments: peroneal nerve between ankle and fibular head, median nerve between wrist and elbow, and ulnar nerve between wrist and below elbow. (2) Conduction velocity must be abnormal in at least 2 motor nerves. This is defined as a reduction in velocity less than 80% of the lower limit of normal if the compound muscle action potential amplitude (CMAP) amplitude is greater than 80% of the lower limit of normal or as a reduction in velocity less than 70% of the lower limit of normal if the CMAP amplitude is less than 80% of the lower limit of normal. (3) The distal latency must be abnormally increased in at least 13

14 two nerves. This is defined as prolonged more than 125% of the upper limit of normal if the CMAP is greater than 80% of the lower limit of normal and l50% if the CMAP is less than 80% lower than normal. (4) F-wave latency must be abnormal in at least two motor nerves. This is defined as an absent or prolonged F-wave more than 125% of the upper limit of normal if the CMAP amplitude is more than 80% of the lower limit of normal or more than 150% of the upper limit of normal if the CMAP amplitude is less than 80% of the lower limit (Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. 1991). (Table 2: Comparison of the diagnostic criteria) Only one to two thirds of patients with the diagnosis of CIDP made by a neuromuscular specialist fulfil the AAN electrodiagnostic criteria (Magda, Latov, Brannagan III et al, 2003; Sander & Latov, 2003). There are several reasons for this. (1) There are insufficient fibres affected. (2) The demyelination is proximal and therefore out of the field of study. (3) There is severe secondary axonal damage that precludes accurate evaluation of nerve conduction velocities. (4) In sensory nerves the action potentials may be absent due to temporal dispersion demyelination and therefore not be documented (Sander et al, 2003). The restrictive nature of the AAN criteria led to other groups developing more sensitive criteria. These include the Nicolas, INCAT (Inflammatory Neuropathy Cause And Treatment) and Saperstein Criteria (Hughes, Bensa, Willison et al, 2001; Saperstein, Katz, Amato et al, 2001; Nicolas, Maisonobe, Le et al, 2002). The Nicolas criteria are purely electrodiagnostic and therefore not appropriate to this clinically based study. Therefore they will not be considered further. 14

15 The INCAT criteria are less stringent than the AAN or Saperstein criteria and do not require CSF testing or nerve biopsy. The Saperstein criteria are similar to the AAN criteria but only require two of the electrodiagnostic features and a biopsy is not mandatory for the diagnosis. Since Dyck et al. described the first cases of CIDP in 1975 the CSF parameters have been a major component of the diagnostic criteria. In the 53 patients collected over 10 years, 44 had CSF results. The CSF protein was raised in 40 of the 44 patients (90%) at some stage in their disease, where a protein of more than 0.45g/l was considered increased. The average was 1.4g/l. The electrophoresis of the CSF protein showed raised IgG. The average number of white cells, including lymphocytes and neutrophils was 4.26 /mm 3. In central nervous system infections typically the CSF protein and white cell count increase together, but in CIDP the protein rises out of proportion to the cell count. This is referred to as cytoalbuminological dissociation. In the second of the large studies that provided a detailed demographic profile of patients with CIDP, Barohn et al. examined CSF protein levels in 59 of the 60 patients in the study. A raised protein was considered to be greater than 0.45g/l. The CSF protein was raised in 56 out of the 59 patients (95%) and the average white cell count was 1.7/mm 3. They did not perform protein electrophoresis on the CSF (Barohn et al, 1989). The AAN Criteria require the white-cell count to be less than 10/mm 3, a negative syphilis serology test, and protein above 0.45g/l to diagnose CIDP. These criteria were used in two large prevalence studies from England and Australia but the CSF protein means were not reported (Lunn et al, 1999; McLeod et al, 1999). 15

16 The INCAT criteria recommend a raised CSF protein for the diagnosis but it is not mandatory. In the Saperstein criteria the CSF protein should be more than 0.45 g/l and a white-cell count of less than 10/mm 3 is supportive. A nerve biopsy is considered an essential part of the AAN criteria (1991). Molenaar et al. combined clinical features, nerve conduction tests, CSF proteins and treating neurologists clinical opinion and assessed whether the a sural nerve biopsy added to, or changed the diagnosis (Molenaar, Vermeulen, & de Haan, 1998). They concluded that nerve biopsy did not add any additional value when making the diagnosis of CIDP. Although research criteria for enrolment in clinical studies need to have a high specificity, clinical criteria should be more sensitive to allow the identification of patients who may need treatment (Magda et al, 2003). Therefore the choices of criteria used in this study are based on our departmental guidelines. We routinely do electrodiagnostic testing and CSF analysis in our department and use the Saperstein criteria for the diagnosis of CIDP. However, if the clinical history, examination and the nerve conduction studies fulfil the criteria and the CSF is normal, we are inclined to ignore it as we feel uneasy denying patients treatment in the face of other convincing evidence of CIDP. We do not perform nerve biopsies routinely in keeping with the findings of Molenaar et al. (Molenaar et al, 1998) More recently the European Federation of Neurological Societies has published a consensus set of diagnostic criteria. These were not available at the time that this study was initiated and therefore were not used. They closely resemble the INCAT criteria. These 16

17 guidelines are very useful in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy and are based on the available evidence and, where adequate evidence was not available, consensus (EFNS/PNS CIDP Guidelines; 2005) Table 2: Comparison of the diagnostic criteria of CIDP (Adapted from Koller et al.) Feature AAN Criteria INCAT Criteria Saperstein Criteria Clinical Involvement Motor dysfunction and/or sensory dysfunction of more than 1 limb. Reflexes are reduced or absent. Progressive or relapsing motor and sensory dysfunction of more than 1 limb. Reflexes are reduced or absent. Major: symmetric proximal and distal weakness. Minor: exclusively distal weakness or sensory loss. Reflexes are reduced or absent. Time course (in months) 2 >2 2 Electrodiagnostic test results Any 3 of the following 4 criteria: 1- Partial conduction block of 1 motor nerve. Partial conduction block of 2 motor nerves AND abnormal conduction velocity OR distal latency OR F-wave latency in 1 other nerve is required. Two of the 4 AAN electrodiagnostic criteria. 2- Reduced conduction velocity of 2 motor nerves. 3- Prolonged distal latency of 2 motor nerves. 4- Prolonged F-wave latencies of 2 motor nerves or the absence of F waves. (Details and definitions are listed above) In the absence of partial conduction block an abnormal conduction velocity, distal latency or F-wave latency in 3 motor nerves is required; OR electrodiagnostic abnormalities indicating demyelination in 2 nerves and histological evidence of demyelination. Cerebrospinal fluid White-cell count <10/mm 3 and negative VDRL test are mandatory and elevated protein level is supportive. Protein >45 mg/dl is mandatory and white-cell count <10/mm 3 is supportive Cerebrospinal fluid analysis recommended but not mandatory Biopsy Evidence of demyelination and Remyelination is mandatory. Predominant features of demyelination; inflammation is supportive but not required. Not mandatory unless there are electrodiagnostic abnormalities in only 2 motor nerves. 17

18 Pathophysiology The aetiology of acquired demyelinating polyneuropathies is presumed to be autoimmune or dysimmune (Koller, Kieseier, Jander et al, 2005). Unlike AIDP there is no clear association between the CIDP and antecedent infections. It is likely that myelin proteins act as a target for the immune system in CIDP. When mice are inoculated with the P 0 protein, a major myelin protein, they develop demyelination and conduction blocks (Yan, Archelos, Hartung et al, 2001). It is thought that an auto-antigen activates T lymphocytes in the in the blood. These activated T lymphocytes then cross the blood nerve barrier in a complex process involving cellular adhesion molecules, matrix metalloproteinases, and chemokines (Quattrini, Previtali, Kieseier et al, 2003). Within the peripheral nervous system, T cells activate macrophages that enhance phagocytic activity, cytokine production, and the release of toxic mediators, including nitric oxide, tumour necrosis factor alpha and interferon gamma (Oka, Akiguchi, Kawasaki et al, 1998). These activated T cells also induce autoantibody production. These are produced by plasma cells and contribute to demyelination and axonal damage via the complement pathway or direct adhesion to membrane channels (Quattrini et al., 2003) Pathology The hallmark of CIDP is demyelination that is multifocal. In one large series of biopsies in patients with CIDP, demyelinating features were seen in only 48%, 21% had predominantly axonal changes, 13% had mixed demyelinating and axonal changes, and 18% were normal (Barohn et al, 1989). There may be other evidence of inflammation like endoneural and subepineural oedema, T lymphocyte and macrophage infiltrates and histochemical staining 18

19 may be positive for cytokines like TNF alpha. Remyelination is seen in advanced cases of CIDP and is evidenced by onion bulb formation (Dyck et al, 1975) Disease course It has been noted that CIDP can follow a steadily progressive, recurrent, stepwise progressive or monophasic course. In two studies patients were divided into recurrent and not recurrent (Table 3. Clinical Course). There is a large variation between each of the papers and this is in part due to patients being treated prior to the studies and this changes the course of the illness (Lunn et al, 1999; McLeod et al, 1999). The variation or difference found might be explained, at least in part, by prior treatment. In an attempt to avoid the impact of treatment on our patients course, we documented their temporal course prior to initiating treatment CIDP Subtypes Since the 1950 s other forms of acquired demyelinating polyneuropathies have been described that differ from classic chronic inflammatory demyelinating polyneuropathy, both with respect to clinical presentation and in their response to treatment. It is not clear whether these conditions are variants of chronic inflammatory demyelinating polyneuropathy or distinct disease entities as there pathophysiology is not fully understood. These conditions are occasionally classified together because they have similar electrophysiological findings and can be treated with immunotherapy. ( (Table 4. CIDP Subtypes) 19

20 Table 4: CIDP subtypes (Adapted from Neuropathy Clinical Features Electrodiagnostic Testing Treatment Antibody CIDP 1-Motor > Sensory 2-Weakness: Proximal & Distal Symmetric 3-Age: 1-80 years 4-Chronic or Relapsing 1-Motor + Sensory changes 2-Slow velocities 3-Conduction Block 4-Distal Latency: Long 5-Slow F-waves 1-Prednisone 2- IVIG 3-Plasma exchange 4-?Chemotherapy? Multi-focal Acquired Demyelinating Sensory And Motor (MADSAM) 1-Motor > Sensory 2-Weakness: Distal > Proximal Asymmetric Arms > Legs 3-Age: years 4-Chronic 1-Motor + Sensory changes 2-Slow velocities 3-Conduction Block 4-Distal Latency: Long 5-Slow F-waves 1-Prednisone 2- IVIG 3-Plasma exchange 4-?Chemotherapy? Distal Acquired Demyelinating Symmetrical (DADS) 1-Sensory predominant 2-Symetrical 3-Age: years 4-Chronic or Relapsing 1-Motor + Sensory changes 2-Slow velocities 3-Conduction block rare 4-Distal Latency: Long 5-Slow F-waves 1-Prednisone 2- IVIG 3-Plasma exchange 4-?Chemotherapy? Multifocal Motor Neuropathy with conduction blocks. (MMN) 1-Motor only 2- Weakness: Distal > Proximal Arms > Legs Asymmetric 3-Age: years 4-Progressive 1-Motor changes only 2-Slow velocities 3-Conduction Block 4-Distal Latency: Long 5-Slow F-waves 1- NOT Prednisone 2- IVIG 3-Plasma exchange 4-?Chemotherapy Anti GM1 Ataxic CIDP (Anti GM2) 1-Sensory > Motor 2-Ataxia: Limb & Gait Distal Symmetric or Asymmetric 3- Adult 4-Progressive 1-Motor + Sensory changes 2-Slow velocities 3-Conduction Block 4-Distal Latency: Long 5-Slow F-waves 1-?Prednisone 2- IVIG 3-Plasma exchange 4-?Chemotherapy Anti GM2 and GalNAc-GD1a 20

21 Neuropathy Clinical Features Electrodiagnostic Testing Treatment Antibody Gait disorder Auto antibody Late age Onset Polyneuropathy (GALOP) 1-Sensory > Motor 2-Ataxic gait Distal Symmetric 3-Age: > 50 years 4-? 1-Motor + Sensory changes 2-Slow velocities 3-Conduction Block 4-Distal Latency: Long 5-Slow F-waves 1-?Prednisone 2-?IVIG 3-Plasma exchange 4-?Chemotherapy Membrane Sulphatide antibody Polyneuropathy Organomegaly Endocrineopathy M-protein Skin changes (POEMS) 1- Sensory and Motor 2-Symmetric 3-Age: years 1-Motor + Sensory changes 2-Slow velocities 3-No Conduction Block 4-Distal Latency: Long 5-Slow F-waves 1-Prednisone 2- IVIG 3-Plasma exchange 4-?Chemotherapy 5- Removal of tumour? CIDP and concurrent illness CIDP may be also associated with concurrent illness for example, viral diseases like HIV and hepatitis C, inflammatory diseases like Sjögren s syndrome and inflammatory bowel disease and neoplasms like melanoma and lymphoma. The relevance of such concurrent diseases is unclear. Monoclonal gammopathy of unknown significance (MGUS) is also associated with CIDP and here the pathology may be due to myelin and auto-antibody interaction (Gorson, Allam, & Ropper, 1997). The association with diabetes mellitus is very important because CIDP occurs more commonly among patients with diabetes (Stewart, McKelvey, Durcan et al, 1996). This 21

22 creates diagnostic and management difficulty as diabetic patients often have pre-existing neuropathy and use of prednisone in the treatment of CIDP makes glycaemic control difficult. CIDP may develop in conjunction with another polyneuropathy, even one with a hereditary basis, such as Charcot Marie Tooth disease (Ginsberg, Malik, Kenton et al, 2004). While the association between acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and HIV is well established, the association of CIDP and HIV is less so. The first case of AIDP associated with AIDS was described in Cornblath described three patients with AIDP preceding the diagnosis of AIDS in 1987 (Ferrari, Vento, Monaco et al, 2006). Later studies confirmed the observation that AIDP occurs early in HIV-1 infection before severe immunosuppression (Vendrell, Heredia, Pujol et al, 1987). In a large series of 32 patients with AIDP in Zimbabwe, all 16 HIV-1-positive patients developed AIDP before the diagnosis of AIDS (Thornton, Latif, & Emmanuel, 1991). The original description of HIV and CIDP occurring together was in 1987 (Cornblath, McArthur, Kennedy et al, 1987). (Search 2) In a study from 2003, 10 patients with AIDP also had HIV and only 40% developed AIDP after onset of AIDS (CD4 T-cell count <200/ml). Three of these patients went on to develop CIDP. This study also showed that cerebrospinal fluid pleocytosis was not always present in HIV-associated AIDP (Brannagan III & Zhou, 2003). The CSF pleocytosis in HIV associated CIDP was considered one of the distinguishing features from CIDP patients without HIV. 22

23 Little has been published about the South African experience of CIDP. The Kwazulu-Natal experience has been alluded to in a recent review paper. Twenty-four HIV positive patients were seen over a 10-year period with CIDP. Clinical features were identical in the HIV and non-hiv patients except for the presence of a mild lymphocytic pleocytosis in the CSF in the HIV positive patients. All patients responded well to treatment. The description does not provide details of the patients CD4 counts, race, age or gender (Bhigjee, 2005). Despite there being very little in the literature about the HIV-associated CIDP there are some important differences that have been noted. The CSF protein level is often raised throughout the course of HIV (Marshall, Brey, Cahill et al, 1988). The protein level does not however correlate with the degree of the distal sensory polyneuropathy seen in HIV (Barohn, Gronseth, Amato et al, 1996). The classic cytoalbuminological dissociation is not always seen in HIV-associated CIDP (Cornblath et al, 1987). HIV has been isolated from nerves of patients with CIDP (Dalakas & Pezeshkpour, 1988). Cytomegalovirus was isolated from nerves of patients with HIV-associated CIDP but not in the non-hiv type (Grafe & Wiley, 1989). Pathologically these nerve biopsies are similar, showing segmental demyelination with an inflammatory infiltration of monocytes in the endo- and epineurium (Cornblath et al, 1987). In the original article describing the association between CIDP and HIV, Cornblath et al. found a male predominance. The majority of these patients had risk factors for HIV namely being male homosexuals or intravenous drug users. The prognosis for patients with both HIV and CIDP seems to be similar to the non-hiv patients with CIDP. Patients who show a progressive course are amenable to the standard forms of treatment but given the 23

24 immunosuppressive nature of these, Cornblath recommended that patients should be monitored closely (Cornblath et al, 1987) Treatment Corticosteroids, plasmapheresis, and IVIg are all effective treatments in CIDP. Individual patients, however, may differ in response to any one of these treatments (Gorson et al, 1997). A single randomised controlled trial provided weak evidence to support the use of corticosteroids in CIDP and subsequent studies have shown that there is no significant difference between the treatment modalities (Gorson et al, 1997; Sghirlanzoni, Solari, Ciano et al, 2000; Mehndiratta & Hughes, 2002). The principal of treatment is to block the inflammatory process and thereby prevent further demyelination and secondary axonal loss leading to permanent disability (Gorson et al, 1997; Sghirlanzoni et al, 2000; Koller et al, 2005) Prognosis In a series of 83 patients evaluated on average 6 years after onset, 56% had good outcome, 24% deteriorated and failed to respond to all treatments, and 11% died of complications of the disease. Axonal loss on the nerve biopsy correlated with poorer outcome (Bouchard, Lacroix, Plante et al, 1999; Sghirlanzoni et al, 2000). In a more recent study the prognosis seemed to be more favourable with 39% of patients still requiring immune treatments and 13% having severe disabilities (Kuwabara, Misawa, Mori et al, 2006). The literature suggests that early treatment may be helpful in improving prognosis by avoiding axonal damage, though there are no randomised data yet to support this. 24

25 2. Aim of the Study In the literature are several studies that describe the clinical presentation and diagnostic criteria for CIDP. However, these studies have been done in high-income countries and in predominantly caucasian populations. South Africa, a middle-income country with a high prevalence of HIV and multiethnic population provides an ideal setting to add information to the literature. Our aim was to describe the clinical features, cerebrospinal fluid findings and electrophysiological examination in an urban, hospital-based, South African population. 3. Design This is a descriptive study combining retrospective case review and prospective assessment of patients with CIDP referred to the Johannesburg Hospital Division of Neurology Population and case ascertainment We based our study at the Johannesburg Hospital, a 1088 bed academic referral hospital that provides health care to predominantly indigent patients. The hospital also provides care at a primary and secondary level to much of the population of Johannesburg. Patients with CIDP were ascertained from the Johannesburg, Chris Hani Baragwanath and Helen Joseph Hospital neurology services. Patients with CIDP reached these services either by direct referral or indirectly via other medical departments. 25

26 3.2. Duration of the study Patients were ascertained and assessed from 1 st January 2005 to 31 st December 2006 (24 months) Assessment of patients All patients were examined by at least one neurologist. Nerve conduction studies were done at the Johannesburg Hospital by a neurologist or a neurology registrar who was supervised by a neurologist. Lumbar punctures and blood tests were done at the Johannesburg Hospital and analysed at the National Health Sciences Laboratory. The first four patients were studied retrospectively the remaining 22 were studied prospectively Inclusion Criteria Patients were included if they gave informed consent to take part in the study, provided they fulfilled the Saperstein criteria for CIDP. These criteria include mandatory clinical, electrodiagnostic, and supportive cerebrospinal fluid criteria, as well as a time course of greater than two months progression. Patients were entitled to withdraw consent or refuse any of the investigations. If they did this we excluded them from the study. One patient refused to take part but received the same standard treatment. 26

27 3.5. Ethics Approval from the Johannesburg Hospital was obtained in writing to proceed with the study. The study protocol, data collection sheet, consent form and information sheet were approved by the University of the Witwatersrand Ethics Committee and Postgraduate Committee. All patients, both retrospectively and prospectively studied signed consent Statistical analysis Statistical analysis was performed using Stata (Stata Corp Stata Statistical Software: Release 10. College Station, TX: Stata Corp LP.). 4. Results 4.1. Demographics Number of patients: Twenty-six patients were diagnosed with CIDP over a two-year period (1 January 2005 to 31 December 2006). Gender of patients: Eight were male and 18 were female. (Ratio male to female - 1:2.25) Age of patients: The range of the ages was 12 to 74 years of age. The average age was 41 years with a standard deviation of 18, 37 years (Graph 1). 27

28 Graph 1. Age No. of Pts Series1 Centiles Ethnicity of patients: There were 16 black patients, 4 white, 6 Indian and no mixed ancestry patients Latency The duration of weakness prior to presentation i.e. latency to presentation was divided into 2 groups months 17 patients 2. > 12 months 9 patients 4.3. Course The course of CIDP was as follows: 1. Relapsing remitting course 50% 2. Progressive course 50%. The average age of the relapsing and remitting group was years (standard deviation ) and years (standard deviation-15.46) for the progressive group. 28

29 Analysis of the association between latency to presentation and time course of illness by Pearson chi-square test reveals a statistically significant correlation with 65% of patients with a progressive course presenting within one year of symptom onset (p = 0.039). No statistically significant difference could be found by two-sample t-test when comparing the age of patients with the course of their illness. This was confirmed using the twosample Wilcoxon rank-sum (Mann-Whiney) test Motor findings The majority of the patients had the characteristic motor signs of proximal and distal weakness in the lower limbs and only distal weakness in the upper limbs except for three. All three of these patients had distal weakness as the dominant feature and two of them also had an asymmetrical presentation and were male. Areflexia was common to all 26 patients. Neck flexion weakness was found in 19 of the patients. There were 8 patients who presented unable to stand, 3 could stand unaided but not walk, 11 had a high stepping gait, 3 had a completely normal gait and 1 was ataxic and could stand. Patients were grouped into ambulatory (14 patients) and non-ambulatory (12 patients) for statistical analysis. Using the Pearson chi-square test no association was found between latency to presentation and severity in terms of ambulation. 29

30 4.5. Sensory Findings Most of the patients had mild sensory signs of loss to pain and temperature except 3 patients who had no sensory signs. These included the two male patients mentioned above who had an asymmetrical presentation. Another patient had a predominantly ataxic presentation with loss of joint position sense up to the knee and pseudoathetosis Cerebrospinal Fluid Findings The range of CSF proteins was 0.11 to 1.96g/l with an average of 0.54g/l (standard deviation of 0.47). Only 42 % had a CSF protein greater than the normal of 0.45g/l. Blood brain barrier (BBB) studies were done in 15 of the 26 patients. The protein levels corresponded well between the standard test and the BBB study (Graph 4). Graph Comparison Of Proteins g/l LP Protein BBB Prot Patients To determine the level of agreement between the standard CSF protein test and the BBB study the intra class/cluster correlation coefficient was determined (maximum value = 1). The intra class/cluster correlation coefficient in this study for the two methods was indicating a very high level of agreement. Ten of the 15 patients had a raised intrathecal IgG synthesis rate, 5 with normal protein levels. Another 5 patients had raised intrathecal 30

31 IgG synthesis rates and raised CSF proteins. The remaining 5 either had BBB damage or were indeterminate. (Table 6) CSF Prot Alb IgG Table 6. Blood Brain Barrier results Serum Alb Key: Alb - Albumin BBB# - Blood Brain Barrier damage CNS - Central Nervous System IgG Synth - IgG Synthesis rate? - Indeterminate IgG IgG Index Alb Index IgG Synth rate Result interpretation? Trauma or CNS IgG or BBB# CNS IgG production CNS IgG Production CNS IgG Production CNS IgG Production CNS IgG Production CNS IgG Production ? CNS IgG Production BBB Damage CNS IgG Production CNS IgG Production ? Trauma or CNS IgG or BBB#? Trauma or CNS IgG or BBB# CNS IgG Production? Trauma or CNS IgG or BBB# 4.7. Concurrent illness Diabetes was present in 4 of the patients and 10 had HIV. None of the patients had both of these conditions. All 10 HIV positive patients were black females of the ages 20 to 63 (average 38.3 years with a standard deviation of years). Their CD4 counts ranged from 87 to 747x10 6 /l (average x10 6 /l with a wide standard deviation of x10 6 /l). The CSF proteins of the HIV-associated CIDP were raised in 40% of patients as opposed to 43.75% of the non-hiv patients. By Fisher s exact test this is not statistically significant (p = 1.00). This was confirmed with Pearson chi-square test (p = 0.851). Mitral stenosis and glaucoma were also found in patients 1 and 14 respectively. 31

32 4.8. Electrophysiology All of the patients fulfilled the electrophysiological diagnostic criteria for CIDP when using the Saperstein criteria. This has been described in detail above. The lowest conduction velocities were taken from the ulnar and peroneal nerves because these nerves are not as prone to technical difficulties as the median and tibial nerves. The average velocities were 28.54m/s for the ulnar nerves and 26.09m/s for the peroneal. (Table 5) Table 5: Nerve Motor Conduction Velocity results Patient Number Ulnar Nerve (m/s) Peroneal Nerve (m/s) 1 30 Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Average

33 Normal Velocity Values: 1- ulnar nerve - >45.0 m/s 2- peroneal nerve - >40.0 m/s Reference: Preston D & Shapiro B: Electromyography and Neuromuscular Disorders Clinical-Electrophysiological Correlations, Second Edition Antibodies There were only 3 patients that had an asymmetrical presentation. All three were males who did not have the classic mixed motor and sensory CIDP but clinically had multifocal motor neuropathy with conduction blocks. None of these patients received steroids. There was one patient with the rare ataxic variant of CIDP. None of our patients had DADS or MADSAM neuropathy. Two patients had positive antibodies on serum testing. Patient 9 was a 53-year-old Indian male and was positive for GM1 antibodies. He was diagnosed with multifocal motor neuropathy with conduction blocks. There were two other patients who had pure motor syndromes clinically and electrophysiologically but both were negative for GM1 antibodies. The second patient with a specific antibody was patient number 6, a white 68- year-old female who presented with a severe sensory ataxia. She tested positive for GM2 anti bodies HIV and CIDP Ten of our 26 patients with CIDP were HIV infected. There are several differences between the HIV negative and positive groups. 33

34 Demographics HIV-ve HIV+ve Number of patients The average ages years 38.3 years Ethnicity Black 6 10 Indian 6 0 White 4 0 No statistically significant difference was found by student t-test (p =0.57) or Mann- Whitney test (p = 0.52) when comparing the ages of the HIV positive and negative groups History and course of weakness HIV-ve HIV+ve Progressive course 6 patients 7 patients Average age with progressive course 52 years years Relapsing remitting (RR) course 10 patients 3 patients Average age with RR course 37.2 years 47 years Seven of the 10 HIV positive patients followed a progressive course and they appear to be younger. When testing whether HIV status influences whether the condition is progressive or relapsing, no statistically significant difference was found by chi-square test (p = 0.107). 34

35 To analyse whether there is an association between HIV status and the age of patients with a progressive or a relapsing course a two way anova was performed. Although not statistically significant (p = 0.191) there is a strong indication of interaction between progression and HIV status being present for age. In particular a progressive course is more likely in older HIV positive patients CIDP Subtype HIV-ve HIV+ve Classic CIDP MMN with anti-gm1 +ve 1 0 MMN with anti-gm1 ve 2 0 Ataxic CIDP with anti-gm2 +ve 1 0 MADSAM 0 0 DADS 0 0 If CIDP sub-types are reduced to 2 groups, classic CIDP and variant CIDP, there is a marginally significant association between HIV status and CIDP subtype. HIV positive patients tend to present with classic CIDP (p = 0.086, chi-square test) Motor HIV-ve HIV+ve Number of patients unable to sit 1 0 Number of patients able to sit unaided 5 3 Number of patients able to stand only 1 2 Number of patients with high stepping gait

36 Number of patients with an ataxic gait 1 0 Number of patients with a normal gait Sensory All of the HIV positive patients had a glove and stocking sensory loss to pain and temperature Cerebrospinal fluid HIV-ve HIV+ve Average protein 0.51g/l 0.57g/l Number of patients with protein > 0.45g/l 7 4 Average Glucose 3.89 mmol/l 3.16 mmol/l Average Chloride mmol/l mmol/l Average Polymorphs count 0.19 x 10 6 /l 0.5 x 10 6 /l Average Lymphocytes count 0.81 x 10 6 /l 16.6 x 10 6 /l By two sample t-test with equal variances there were no statistically significant differences between HIV positive and HIV negative patients with respect to CSF protein (p = 0.381) or glucose (p = 0.967). CSF chloride was significantly higher in the HIV positive group (p = 0.023), but both were in within the normal range for our laboratory ( mmol/l). Cytoalbuminological dissociation was present in all 16 HIV negative patients and in 7 of the 10 HIV positive patients. Using Pearson s chi-square test, the absence of 36

37 cytoalbuminological dissociation is strongly associated with HIV positive status (p = 0.020). 5. Discussion CIDP remains a relatively unknown condition. Apart from neurologists, most clinicians are unaware of the existence of the condition. The old term of Chronic Guillain-Barré Syndrome is still adhered to, other than in neurological circles. There is a lack of awareness of CIDP variants, which now include specific antibody testing. The evolution of this disease has created problems with the diagnosis and diagnostic criteria as described above. This problem is primarily responsible for what may be an underestimation of the condition s prevalence. (Dyck, Lais, Ohta et al, 1975; Dyck, Oviatt, & Lambert, 1981; Gorson, Allam & Ropper, 1997; Koller, Kieseier, Jander et al, 2005). There are two prevalence studies, one from Australia the other from the United Kingdom (Lunn, Manji, Choudhary et al, 1999; McLeod, Pollard, Macaskill et al, 1999). Both of these studies used very strict diagnostic criteria for CIDP. The prevalence is thought to be about 1: These studies are also based on a limited number of cases. There is very little information about the condition in Africa and no studies have been done at all in Sub Saharan Africa (Search 1.) Obtaining large number of cases of CIDP is difficult. In the original Dyck et al. paper from 1975, 53 patients were collected over a 10-year period from several centres and Barohn et al. (1989) collected 60 patients from a specialized neuromuscular unit over 10 years. We were able to collect 26 patients over a 2-year period from the greater Johannesburg area. 37

38 This number may be an insufficient sample size to derive robust statistical information but this study will nevertheless contribute numbers to the CIDP body of knowledge and particularly on CIDP in Africans Demographics Gender Ratio According to the literature there is a male predominance in patients with CIDP of approximately 2:1. In our case series we found that 8 out of the 26 patients were male which gives a reverse ratio of 2.25 females to one male. This may be co-incidental and be a reflection of small sample size. A hypothetical alternate explanation may be the relationship to the HIV epidemic. As in the rest of sub-saharan Africa, the epidemic in South Africa disproportionately affects women. Young women (15 24 years) are four times more likely to be HIV-infected than are young men: in 2004, prevalence among young women was 17% compared with 4.4% among young men (Connolly, Shisana, Colvin et al, 2004). We found that 38.46% of our patients were HIV positive and all were female. There were 16 HIV negative patients, with 8 males and 8 females, giving a 1:1 ratio that is closer to the gender ratio seen in the literature Ethnicity 38

39 Ethnicity has not previously been documented in the literature and all the pivotal studies do not mention ethnic backgrounds of patients. In our study we divided patients on the basis of ethnic backgrounds and found that there were 16 Black patients, 4 White, 6 Indian and no patients of mixed ancestry. This demographic distribution is a fair reflection of the population in South Africa. Patients with HIV and CIDP were all black. This again may be co-incidental or more likely is a reflection of the HIV epidemic in South Africa (Connolly, 2001) Age Our patients had an earlier age of onset compared to the literature. The average age of our group was 41 years. In the international literature the age of onset is older than this, usually in the 50 th to 60 th decades (Table 2). When the HIV positive patients are separated from the rest of the group they are slightly younger at 38.3 years compared to 41.2 years in the HIV negative group (Graph 2). Overall, our patients are younger even when the HIV patients are discounted. This may be co-incidental or represent the profile of CIDP in African patients Latency The duration of weakness prior to presentation was divided into 4 groups. Twelve patients presented from 2 to 6 months from the onset of their symptoms, 5 patients from 6 to 12 months, 2 patients from 12 to 24 months and 7 patients presented more than two years from the onset of their symptoms. 39